Abstract/Summary

Platelets play a crucial role in haemostasis and thrombosis, and their activation is regulated by various agonists and intracellular signalling pathways. This PhD thesis aims to investigate the complex interplay between platelet receptors, signalling pathways, and intracellular calcium dynamics using mathematical modelling approaches. We present an agent-based model (ABM) to investigate the dimerisation of GPVI and the role of glycolipid-enriched raft-like domains in regulating receptor diffusion. We introduce an ordinary differential equation (ODE) model to unravel the regulatory mechanisms of GPVI signalling from Syk phosphorylation to releasing inositol trisphosphate (IP3) into the platelet cytosol via LAT signalosome. To fulfil the signalling complexity more completely than has previously been possible, a mathematical model of phosphoinositide (PI) metabolism in human platelets in response to GPVI activation was developed and calibrated against experimental data capturing transient time-course changes in phosphoinositide positional isomers. Finally, two machine learning models, a non-linear autoregressive network with exogenous inputs (NARX) and a partial least square (PLS) regression model, were developed to investigate how different agonists and inhibitors impact on intracellular calcium dynamics in platelets. The findings from this thesis provide valuable insights into the complex regulatory mechanisms of platelet activation and intracellular calcium dynamics and how they are influenced by various agonists and inhibitors. These mathematical modelling approaches have the potential to be used in the development of simulation frameworks for studying spatiotemporal concentrations of ligands and inhibitors in platelets. The results of this thesis may have implications for the development of targeted therapies for platelet-related diseases, such as thrombosis and haemostasis disorders. The models also have wide applicability to other cell systems. Overall, this PhD thesis contributes to our understanding of platelet biology and provides novel insights into platelet signalling and calcium dynamics using mathematical modelling approaches.